The renin-angiotensin system (RAS) plays an integral role in cardiovascular homeostasis through its effects on vascular tone and volume, and pharmacological interruption of this system has found widespread clinical application. Independent of the effects of the RAS on blood pressure, activation of this system has been identified as a risk factor for the development of ischemic heart disease. Although multiple mechanisms may be responsible for this association, we have focused on the effects of the RAS on the plasminogen activator system, which serves as one of the major endogenous defense mechanisms against intravascular thrombosis and also plays an important role in vascular and tissue remodeling. The central hypothesis of this proposal is that a major component of the vascular toxicity brought on by activation of the RAS is derived from the deleterious effects of angiotensin on fibrinolytic balance. A multifaceted research strategy involving in vitro and in vivo experiments is described to test this hypothesis. The specific aims of this proposal are the following: 1) to test the hypothesis that angiotensin land bradykinin modulate fundamental peripheral circadian oscillating mechanisms that regulate PAl-1 production in vitro; 2) to characterize the role of angiotensin and the All receptor in promoting PAl-1 expression in response to chronic nitric oxide synthase inhibition; and 3) to study the effects of angiotensin II alone and in combination with hypercholesterolemia on the development of coronary thrombosis in transgenic mice that over express a stable form of human PAl-1. It is anticipated that these studies will generate important new information regarding the interactions of the RAS, the vascular endothelium, and fibrinolysis. Furthermore, this project may contribute to our understanding of the regulation of two systems that play vital roles in cardiovascular homeostasis, and thus may improve our abililty to prevent and treat atherothrombotic cardiovascular disease.